tbuckley/cabot-search huggingface dataset:
Abstract 1741: Inhibition of pcsk9 impairs the development of vessel co-option and potentiates anti-angiogenic therapy in colorectal cancer liver metastases
Authors: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Andrew Reynolds, Anthoula Lazaris, Nabil Seidah, Peter Metrakos
Journal: Cancer Research (2023)

Abstract Colorectal cancer liver metastatic (CRCLM) tumours present as two main histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours obtain their blood supply by sprouting angiogenesis, whereas the RHGP tumours utilize an alternative vascularisation known as vessel co-option. In vessel co-option, the cancer cells hijack the mature sinusoidal vessels to obtain blood supply. Vessel co-option has been reported as an acquired mechanism of resistance to anti-angiogenic treatment in CRCLM. Herein, we show the connection between serum cholesterol concentration and vessel co-option development in CRCLM. Our clinical data suggested that the elevation of serum cholesterol levels correlates with the risk of developing vessel co-opting tumours. Moreover, inhibition of PCSK9, the key modulator of cholesterol metabolism, significantly attenuated the development of vessel co-opting CRCLM tumours and sensitized the tumours to anti-angiogenic therapy in vivo. Altogether, these data suggest the importance of cholesterol in the development of vessel co-option tumours and propose that inhibiting PCSK9 is a promising strategy to overcome resistance to anti-angiogenic therapy in CRCLM. Citation Format: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Andrew Reynolds, Anthoula Lazaris, Nabil Seidah, Peter Metrakos. Inhibition of pcsk9 impairs the development of vessel co-option and potentiates anti-angiogenic therapy in colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1741.
Abstract 1746: Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma
Authors: Carmen Oi Leung, Yang Yang, Karl Kam So, Qian Zhao, Terence Kin Lee
Journal: Cancer Research (2023)

Abstract Lenvatinib is the FDA-approved targeted drug for advanced hepatocellular carcinoma (HCC), but the efficacy is modest due to drug resistance. Tumor kinome re-wiring governs drug resistance in resistant cancer cells, which is an obstacle for efficient cancer therapy. Therefore, identification of the kinases critical for this rewiring process in HCC is crucial. Upon mass spectrometry analysis using a lysine-targeted sulfonyl fluoride probe named XO44, CDK6 was identified to be the most upregulated kinase in lenvatinib-resistant HCC cell lines. Lentiviral-based overexpression and knockdown approaches were performed to characterize functional roles of CDK6 in regulation of cancer stemness and lenvatinib resistance. The upregulation of CDK6 in lenvatinib-resistant HCC cells is found to be mediated by the ERK/YAP signaling cascade. CDK6 is crucial in the regulation of acquired lenvatinib resistance via augmentation of cancer stemness and the overexpression of CDK6 led to poorer patient survival. We identified a novel noncanonical pathway of CDK6 in which it binds and regulates the activity of GSK3β, leading to activation of the Wnt/β-catenin signaling pathway. CDK6 inhibition by CDK4/6 inhibitor palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with lenvatinib in vitro. Interestingly, palbociclib not only exerts the maximal growth suppressive effect with lenvatinib in lenvatinib-resistant HCC xenografts and Trp53KO/MYCOE-induced HCC models but also reshapes the tumor immune microenvironment. CDK6 blockade impedes the lenvatinib-induced activation of the ERK/YAP/CDK6/β-catenin signaling cascade. Targeting CDK6 with palbociclib in combination with lenvatinib may be a novel therapeutic strategy against HCC. Citation Format: Carmen Oi Leung, Yang Yang, Karl Kam So, Qian Zhao, Terence Kin Lee. Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1746.
Abstract 5992: Cells rapidly adapt to CDK2 inhibitors via plasticity of the CDK2/4/6-Rb-E2F axis
Authors: Mansi Arora, Justin Moser, Timothy E. Hoffman, Lotte P. Watts, Mingwei Min, Monica Musteanu, Yao Rong, Jordan Schneider, C Ryland Ill, Varuna Nangia, Manuel Sanclemente, John Lapek, Lisa Nguyen, Sherry Niessen, Stephen Dann, Todd van Arsdale, Mariano Barbacid, Nichol Miller, Sabrina L. Spencer
Journal: Cancer Research (2023)

Abstract CDK2 is a core cell-cycle enzyme that phosphorylates a variety of substrates to drive progression through the cell cycle. CDK2 is hyperactivated in multiple cancers and is therefore an attractive therapeutic target. Here, application of a novel small molecule CDK2/4/6 inhibitor, PF-06873600, enabled in-depth interrogation of CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. CDK2-specific inhibition leads to rapid loss of substrate phosphorylation, but unexpectedly, CDK2 substrate phosphorylation rebounds within several hours. Whereas CDK1 is known to compensate for loss of CDK2 in Cdk2-/- mice, here we demonstrate an early dependence on CDK4/6 activity. CDK2 inhibition reveals latent CDK4/6 activity throughout S phase that backstops the proliferative program by maintaining Rb1 hyperphosphorylation, active E2F transcription, and Cyclin A2 expression, enabling re-activation of CDK2. Our results augment our understanding of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 is required to suppress adaptation to CDK2 inhibitors. Citation Format: Mansi Arora, Justin Moser, Timothy E. Hoffman, Lotte P. Watts, Mingwei Min, Monica Musteanu, Yao Rong, Jordan Schneider, C Ryland Ill, Varuna Nangia, Manuel Sanclemente, John Lapek, Lisa Nguyen, Sherry Niessen, Stephen Dann, Todd van Arsdale, Mariano Barbacid, Nichol Miller, Sabrina L. Spencer. Cells rapidly adapt to CDK2 inhibitors via plasticity of the CDK2/4/6-Rb-E2F axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5992.
Abstract 2431: The role and regulation of YAP1 in paligenosis, the cell program converting mature cells into precancerous metaplasia
Authors: Yongji Zeng, Spencer G. Willet, Yangzhe Huang, Steven Bark, Jason C. Mills
Journal: Cancer Research (2023)

Abstract To advance gastric cancer prevention, diagnosis, and treatment, and understand its origins, we aim to understand why precursor metaplasias form and how they progress to cancer. Paligenosis is a recently characterized conserved molecular process which cells use to convert from normal, differentiated, mature cells into proliferative, progenitor-type cells; in the stomach, paligenosis converts digestive-enzyme-secreting chief cells into Spasmolytic Polypeptide Expressing Metaplasia cells (SPEM). Paligenosis occurs by stepwise series of cellular-molecular events characterized by dynamic regulation of mTORC1: Stage 1, mTORC1 decreases, chief cells scale down their secretory apparatus. Stage 2, SPEM genes are induced. Stage 3, mTORc1 increases and the previously mitotically quiescent cells re-enter the cell cycle. Unregulated or “unlicensed” paligenosis imparts nondividing mature differentiated cells the ability to re-enter the cell cycle despite mutations and other genomic abnormalities, making paligenosis a likely initiating process for gastric cancer. The Hippo pathway regulates cell proliferation and differentiation by phosphorylating the transcriptional co-activator YAP1. YAP1 can also act as an oncogene during tumorigenesis, but the regulation of the Hippo pathway and YAP1 in metaplasia and in paligenosis are still unclear. Here we show that YAP1 accumulates in Stage 2 leading to increased expression of many canonical transcriptional targets including cell cycle genes. Overexpression of YAP-S127A in low-dose-tamoxifen-treated Mist1CreERT2/+; ROSA26LSL-rtTA.IRES.EGFP/+; tetOYap1S127A mice induced by doxycycline is sufficient to induce chief cells to enter mitosis while the deletion of YAP1 in Mist1CreERT2/+; ROSA26LSL-Ai9/+; YAP1flox/flox ; TAZflox/flox mice leads to the failure of chief cells to go through paligenosis. Yap1 mRNA was changed by single-cell RNA sequencing, whereas proteomics with western blot validation showed unchanged total YAP1 protein, suggesting YAP1 may be regulated by subcellular localization. Multi-omic data with western blot and immunohistochemistry validation indicated YAP1 localization is regulated in a Hippo pathway kinase-dependent way and SMAD2/3, key effectors of TGF-β signaling, being potential downstream targets. In summary, our study indicates that YAP1 activity is required for paligenosis, working independently of Hippo and interacting with TGF-β signaling. Citation Format: Yongji Zeng, Spencer G. Willet, Yangzhe Huang, Steven Bark, Jason C. Mills. The role and regulation of YAP1 in paligenosis, the cell program converting mature cells into precancerous metaplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2431.
Abstract 3894: The role of ELF3 in acquired resistance to endocrine therapy in ER-positive breast cancer
Authors: Na Zhang, Rongbin Zheng, Myles Brown
Journal: Cancer Research (2023)

Abstract Endocrine therapies targeting the estrogen receptor (ER) are the major treatments of ER+ breast cancer, however acquired resistance to endocrine therapy is almost unavoidable and is the main cause of death with breast cancer. The only FDA-approved selective estrogen receptor degrader (SERD) fulvestrant has been used in the second line treatment to overcome aromatase inhibitor- or tamoxifen-resistance. However, fulvestrant has poor pharmacokinetic properties, which has inspired the development of a new generation of oral SERDs including amcenestrant and giredestrant. To understand the mechanisms of acquired resistance to SERDs in ER+ breast cancer, we established ER+ breast cancer cell lines (MCF7 and T47D) resistant to fulvestrant, amcenestrant or giredestrant. We found that all of our MCF7 and T47D SERD-resistant cell lines showed cross-resistance to each of the three SERDs. We then performed multiple genome-wide profiling assays including CRISPR-KO screen, whole exome sequencing (WES), RNA-seq, ATAC-seq and H3K27ac ChIP-seq on the parental and SERD resistant cell lines. Our findings from the CRISPR-KO screens suggest that ETS transcription factor ELF3 is a potential driver of resistance to SERDs. ELF3 expression is negatively regulated by estrogen signaling. Cells that developed acquired resistance to different SERDs consistently show depletion of ER expression but also a dramatic increase of ELF3 expression, while knockdown of ELF3 in the resistant cells leads to cell growth inhibition, suggesting that ELF3 can drive cell survival in the SERD resistant cells. When comparing the open chromatin regions and active enhancer regions between SERD resistant and parental cells via ATAC-seq and H3K27ac ChIP-seq respectively, ELF3 DNA binding motif was found significantly enriched in SERD resistant cells versus parental cells further indicating that ELF3 may play an important role in the SERD resistant cells. ELF3 ChIP-seq was also performed to identify genes enriched with ELF3 binding sites in SERD resistant and parental cells. Pathway analysis of ELF3-targeted genes reveals that ELF3 may regulate cell metabolism specifically in SERD resistant cells but not in parental cells. Our study suggests that ELF3 may be a novel driver of acquired resistance to SERDs in ER+ breast cancer. Citation Format: Na Zhang, Rongbin Zheng, Myles Brown. The role of ELF3 in acquired resistance to endocrine therapy in ER-positive breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3894.
Abstract 1071: Tipifarnib synergizes with TKIs in clear cell renal cell carcinoma models
Authors: Jovylyn Gatchalian, Linda Kessler, Stacia Chan, Francis Burrows, Shivani Malik
Journal: Cancer Research (2023)

Abstract Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor type, primarily due to loss of the Von Hippel-Lindau (VHL) gene, which is observed in ~88% of ccRCC cases. Deletion of VHL stabilizes hypoxia-inducible factor alpha protein (HIFα) to drive the hypoxic transcriptional response, including induction of VEGF and PDGF2 that mediate tumor angiogenesis. Anti-angiogenic tyrosine kinase inhibitors (TKIs) such as sunitinib and axitinib have demonstrated therapeutic benefit in patients with ccRCC by exploiting the critical dependency of ccRCC tumors on the vasculature for oxygen, nutrients, and growth factors. However, resistance to TKIs is commonly observed, leading to clinical relapse. Here, we report that the combination of the farnesyltransferase inhibitor (FTI), tipifarnib, and any of several anti-angiogenic TKIs results in deeper and more durable responses in the VHL-mutant 786-O CDX model and an RCC PDX model, compared to TKI alone. While the anti-angiogenic TKIs or tipifarnib alone merely slowed or occasionally arrested tumor growth, the TKI-tipifarnib combination induced marked tumor regressions in all treated animals. To investigate the mechanism of action, VHL-mutant RCC cell lines were subjected to hypoxia (1% O2) in vitro to mimic the hypoxic conditions induced by TKIs in vivo and were treated with tipifarnib to evaluate tipifarnib’s impact on signaling pathways in hypoxia-exposed cells. In the Caki2 cell line, hypoxia initially reduced mTOR signaling, but it rebounded strongly after 24 hours in hypoxia, suggesting that mTOR pathway reactivation is a potential mechanism of resistance to TKIs. Addition of tipifarnib blocked hypoxia-induced mTOR reactivation. Mechanistically, tipifarnib potently inhibits the farnesylation, and hence the activity, of an obligate farnesylated protein RHEB, a positive regulator of mTOR, suggesting that the synergy may arise through RHEB inhibition in this model. The mechanistic data in cell lines suggest that tipifarnib’s ability to inhibit mTOR reactivation observed in ccRCC cell lines under hypoxic stress contributes to the enhanced treatment durability observed in vivo. Because FTIs are pleiotropic drugs, there are likely additional cell intrinsic mechanisms that may influence synergy with TKIs. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of TKI-tipifarnib effects and strengthen the therapeutic rationale for combining TKIs with tipifarnib in the treatment of patients with ccRCC. Citation Format: Jovylyn Gatchalian, Linda Kessler, Stacia Chan, Francis Burrows, Shivani Malik. Tipifarnib synergizes with TKIs in clear cell renal cell carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1071.
Abstract 3285: Targeting TBK1 to overcome resistance to cancer immunotherapy
Authors: Yi Sun, Or-Yam Revach, Seth Anderson, Anne Jenney, Caitlin E. Mills, Payal Tiwari, Robert T. Manguso, Russell William Jenkins
Journal: Cancer Research (2023)

Abstract Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. We identified the innate immune kinase TANK-binding kinase 1 (TBK1) as a candidate immune evasion gene in a pooled genetic screen. Using a suite of genetic and pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNFα/IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumor models. Cancer cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNFα/IFNγ in a JAK/STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy. Citation Format: Yi Sun, Or-Yam Revach, Seth Anderson, Anne Jenney, Caitlin E. Mills, Payal Tiwari, Robert T. Manguso, Russell William Jenkins. Targeting TBK1 to overcome resistance to cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3285.
Abstract 3442: FXR mediates macrophage intrinsic responses to suppress colon cancer progression
Authors: Ting Fu, Xingchen Dong
Journal: Cancer Research (2023)

Abstract Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, regulating epithelium turnover, maintaining microbiota balance, and modulating the immune system. As a master regulator of BAs homeostasis and innate immunity, Farnesoid X Receptor (FXR), is severely compromised in inflammatory bowel disease (IBD) and colitis-associated colorectal carcinoma (CAC) patients. At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BAs-FXR axis in macrophages. To dissect how inflammation drives tumorigenesis, we employed a classic mouse model of CAC, profiled BAs and cytokines, monitored tumorigenesis, and examined the function of macrophages and Th17 cells. Moreover, we investigated the potential of FexD, an FXR agonist, in ameliorating intestinal inflammation, thus inhibiting tumorigenesis. Further, we identified how macrophage intrinsic FXR senses the BAs abnormality and reshapes the gut macrophages in vivo and ex vivo. We also investigated the potential role of pro-inflammatory cytokines in stimulating intestinal stem cells (ISCs)’ stemness using mouse organoids. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs profile in CAC. Gut macrophage intrinsic FXR senses the aberrant BAs, leading to the secretion of pro-inflammatory cytokines, which promotes ISCs’ proliferation. Notably, FexD reduced intestinal inflammation and tumorigenesis by suppressing pro-inflammatory responses in gut macrophages and Th17 cells. Mechanistically, FXR regulates gut macrophages' recruitment, polarization, maturation, and crosstalk with Th17 cells. In summary, we uncovered a novel role of FXR modulation of gut macrophages, highlighting the potential of FXR as a therapeutic target over biologicals for treating colon cancer. Citation Format: Ting Fu, Xingchen Dong. FXR mediates macrophage intrinsic responses to suppress colon cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3442.
Abstract 99: Apoptotic DNase DFFB mediates cancer persister cell mutagenesis and acquired drug resistance
Authors: August Finley Williams, David Gervasio, Claire Turkal, Anna Stuhlfire, Michael Wang, Brandon Mauch, Ariel West, Michelle Paw, Mehrshad Hairani, Cooper Lathrop, Sophie Harris, Jennifer Page, Matthew Hangauer
Journal: Cancer Research (2023)

Abstract Tumors frequently acquire resistance to therapy resulting in disease relapse and patient mortality. Therapeutic approaches to overcome acquired resistance are hindered by limited treatment options and the presence of multiple parallel resistance mechanisms. Rather than treating resistance after it emerges, it may possible to prevent it by inhibiting the adaptive processes which initiate resistance. However, these processes and the genes which control them are poorly understood. Here we report that drug-tolerant cancer persister cells, which constitute residual disease and seed relapse, undergo drug stress-induced sublethal apoptotic signaling resulting in activation of apoptotic DNase DFFB without cell death. DFFB induces DNA damage and mutagenesis in persister cells, revealing DFFB as a key regulator of stress-induced mutagenesis in persister cells. Furthermore, we found in multiple tumor types that DFFB is required for acquired resistance to targeted therapies. Mechanistically, DFFB induces multiple putative resistance mutations and may also promote epigenetic changes which result in resistance. These results reveal DFFB as a promising potential therapeutic target to prevent acquired resistance. In addition, this stress-sensing mutagenic mechanism may promote mutagenesis in other contexts including normal tissues because sublethal apoptotic signaling may result from a variety of physiological stresses. Citation Format: August Finley Williams, David Gervasio, Claire Turkal, Anna Stuhlfire, Michael Wang, Brandon Mauch, Ariel West, Michelle Paw, Mehrshad Hairani, Cooper Lathrop, Sophie Harris, Jennifer Page, Matthew Hangauer. Apoptotic DNase DFFB mediates cancer persister cell mutagenesis and acquired drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 99.